The research in my lab is directed toward understanding the cellular and molecular mechanisms that underlie pain hypersensitivity associated with injury and disease. We focus our efforts on the role of the metabotropic glutamate receptors (mGluRs), which have been the subject of a number of recent studies examining their role in the modulation of pain perception. Evidence suggests that mGlu5 is particularly important in the pathophysiology of inflammatory pain. In work performed under the original term of this grant, we found that blockade of mGlu5 in the spinal cord dramatically reduces pain in behavioral models of inflammation, particularly those thought to involve the sensitization of superficial dorsal horn neurons. Furthermore, we showed that direct activation of mGlu5 in the dorsal horn causes overt nocifensive behaviors similar to those seen in inflammatory pain models, mGlu5 exerts its effects in dorsal horn neurons via activation of the ERK signaling cascade. In patch clamp studies of superficial dorsal horn neurons in culture or in acute spinal cord slice preparations, we have found that activation of mGlu5 dramatically enhances neuronal excitability, and this effect appears to require PKC and ERK-dependent modulation of transient outward K+ currents composed of Kv4 subunits. This increase in excitability is likely to contribute to central sensitization associated with inflammatory pain. Overall, these studies suggest an important role for PKC and ERK signaling and their modulation of Kv4-containing potassium channels in the regulation of nociception by metabotropic glutamate receptor 5. The studies proposed here will test whether modulation of neuronal excitability and nociceptive behaviors by mGlu5 requires PKC- and ERK-dependent mechanisms, and in particular which of the many isozymes of PKC and ERK are involved in this modulation using a variety of knockout and transgenic mouse lines. Furthermore, we will test the hypothesis that a confirmed ERK substrate, the Kv4.2 potassium channel subunit, is involved in the modulation of nociception and dorsal horn neuronal excitability. [unreadable] [unreadable] [unreadable]